tbuckley/cabot-search huggingface dataset:
Abstract 2694: Blockade of the cyclooxygenase-2 prevents chemotherapy-induced cognitive impairments
Authors: Mohammad Abdur Rashid, Jason J. Tang, Ki-Hyun Yoo, Ana Corujo-Ramirez, Sang Hoon Kim, Alfredo Oliveros, Peter Cole, John R. Hawse, Mi-Hyeon Jang
Journal: Cancer Research (2023)

Abstract Chemotherapy-induced cognitive impairment (CICI, also termed “chemobrain”) is a major neurotoxic side effect exhibited by a wide range of chemotherapeutic agents. These side effects affect approximately 14 million cancer survivors. More importantly, CICI persists well after cessation of therapy, severely interfering with quality of life. Unfortunately, there is no treatment and novel therapies are urgently needed. Utilizing cisplatin, a platinum-based chemotherapy, to model chemobrain mice in vivo, we have established that cisplatin accelerates the brain aging process thus leading to long-term memory impairment in mice similar to what is clinically reported. We further show that cisplatin causes oxidative DNA damage, mitochondrial defects, impaired neurogenesis, synaptic defects, and increased gliosis in the adult hippocampus, a brain region critical for learning and memory. Mechanistically, our RNA-sequencing and qRT-PCR analysis revealed that cisplatin dramatically increases COX-2 (Ptgs2) expression and its major product, prostaglandin E2 (PGE2) in adult mouse brain and human cortical neurons derived from induced pluripotent stem cells (iPSCs). Similar as cisplatin treatment, the levels of COX-2 expression began to increase at 0.1 µM methotrexate treatment, which significantly increased at 1 µM in human cortical neurons, indicating that COX-2 induction is a common pathogenic mechanism mediating cognitive impairment associated with cisplatin and methotrexate in spite of the fact that these compounds have different mechanisms of action for cancer eradication. Most importantly, NS-398, a selective COX-2 inhibitor, effectively prevents cognitive deficits in mice and reduction in cell viability of human neurons associated with these chemotherapies, without promoting tumor growth or interfering with cisplatin’s anti-tumor activity. Taken together, our findings strongly suggest that COX-2 induction is a main cause of CICI, making COX-2 inhibition a therapeutic target for CICI. Given that COX-2 inhibitors are currently being tested in cancer prevention as well as age-related memory loss in clinical trials, inhibiting COX-2 may have far-reaching therapeutic effects on CICI and cancer treatment, which can be applied quickly, safely, and effectively to clinical trials, in the effort to improve cancer survivor quality of life. Citation Format: Mohammad Abdur Rashid, Jason J. Tang, Ki-Hyun Yoo, Ana Corujo-Ramirez, Sang Hoon Kim, Alfredo Oliveros, Peter Cole, John R. Hawse, Mi-Hyeon Jang. Blockade of the cyclooxygenase-2 prevents chemotherapy-induced cognitive impairments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2694.
Abstract 5028: The regulation of inflammatory signaling in cancer via A20 phosphorylation
Authors: Tania Lopez Palacios, Tsz-Yin Chan, Christina Egbert, Jacob Truman, Spencer Ashworth, Alec Vaughan, Joshua L. Andersen
Journal: Cancer Research (2023)

Abstract A20 is an anti-inflammatory protein with a dual ubiquitin-editing activity. Through its N-terminal ovarian tumor (OTU) domain, A20 negatively regulates NF-ĸB by removing the K63-linked ubiquitin chains on RIP1 that act as platforms for NF-ĸB activation downstream of tumor necrosis factor alpha (TNFα). On the other hand, A20 also catalyzes the addition of K48-linked ubiquitin chains on RIP1 via its C-terminal zinc finger domain 4 (ZnF4) to promote its proteasomal degradation. Through both mechanisms, A20 is a means of negative feedback on TNFα-induced NF-ĸB activity. Importantly, inactivation of A20 is frequently found in B-cell lymphomas, where loss-of-function A20 truncations promote cell proliferation and upregulation of NF-ĸB signaling. Among the post-translational modifications (PTMs) reported in A20, there are several phosphorylation events in its C-terminus, including within the ZnF4 domain. Besides its known E3 ubiquitin ligase activity, previous reports show that the C-terminal region of A20 is important for ubiquitin binding, having preference for K63-linked poly-ubiquitin. However, a little is known about the effects of phosphorylation at this region on A20 activity as well as its consequences in downstream signaling. Our current work suggests that phosphorylation in the C-terminus of A20 inhibits its E3 ubiquitin ligase activity and disrupts its interaction with ubiquitin, which may also affect its deubiquitinase activity by preventing its recruitment to ubiquitinated proteins in the TNFα receptor (TNFR) complex. We also propose that the C-terminal region is important for the formation of the A20 ubiquitin-editing complex, necessary to downregulate NF-ĸB-activated inflammatory signals. Based on these observations, we hypothesize that not only gene-inactivating mutations, but also post-translational mechanisms, such as phosphorylation, inhibit A20 to promote cancer development. Our research is now focused on understanding the upstream signaling that regulates A20 phosphorylation. Citation Format: Tania Lopez Palacios, Tsz-Yin Chan, Christina Egbert, Jacob Truman, Spencer Ashworth, Alec Vaughan, Joshua L. Andersen. The regulation of inflammatory signaling in cancer via A20 phosphorylation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5028.
Abstract 2355: Transcription factor EB modulates fibrotic response in pancreatic ductal adenocarcinoma
Authors: Alejandra Diaz Alcalde, Edoardo Vallariello, Elena Astanina, Emanuele Middonti, Federico Bussolino
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC), which comprises 85% of all the pancreatic cancers, is one of the most aggressive and deadly tumor that exists today with less than 8% of survival 5 years after diagnosis. It is predicted to become the second cause of cancer death by 2030. A typical characteristic of this tumor is the presence of prominent stroma component mainly produced by Pancreatic Stellate Cells (PSCs) in response to soluble factors released by cancer cells. PSCs activation and differentiation into CAF (Cancer-associated fibroblasts) is a reversible process, which impacts on both tumor progression and drug resistance. Transcription factor EB (TFEB) is mostly known as a master regulator of autophagy and lysosomal biogenesis. A recent study demonstrated that TFEB inhibits epithelial-to-mesenchymal transition (EMT) and myofibroblast differentiation in epicardial cells by upregulating TGIF1, a TGFβ pathway repressor. Based on this observation, we investigated if TFEB might have an inhibitory role in PSCs activation, taking into consideration the crucial role of TGFβ signaling in this process. The TFEB expression, measured by immunostaining, was significantly downregulated in CAFs in human PDAC samples compared to PSCs in healthy pancreas. In PSCs, co-cultured with PDAC cell lines, CAF markers were upregulated while TFEB expression was downregulated. The overexpression of TFEB in PSCs suppressed CAF markers upregulation induced by co-culture with PDAC cells at both mRNA and protein levels. The bulk RNAseq analysis showed the differential expression of genes required for extracellular matrix production, fibrotic response and inflammation in PSCs co-cultured with PDAC cell lines versus PSCs alone, with and without TFEB overexpression. These in vitro data suggest a role for TFEB in PSCs activation and stroma formation which will be further investigated in PDAC mouse models. Citation Format: Alejandra Diaz Alcalde, Edoardo Vallariello, Elena Astanina, Emanuele Middonti, Federico Bussolino. Transcription factor EB modulates fibrotic response in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2355.
Abstract 6014: Cancer risk diagnosis by epimutation burden: a multicenter prospective study
Authors: Harumi Yamada, Masahiro Maeda, Seiichiro Abe, Taichi Shimazu, Takayuki Ando, Kazunari Murakami, Shinji Tanaka, Takao Maekita, Osamu Inatomi, Ken Sugimoto, Tetsuro Kawagoe, Nobutake Yamamichi, Toshikazu Ushijima
Journal: Cancer Research (2023)

Abstract Aberrant DNA methylation, induced by aging and accelerated by chronic inflammation, accumulates in normal tissue. Accumulation of DNA methylation in multiple genes, namely epimutation burden, is closely associated with cancer risk. Indeed, we demonstrated that the measurement of the methylation level of a marker gene in normal tissue is useful for cancer risk prediction of metachronous cancers, by a multicenter prospective study with gastric cancer patients (Asada, Gut, 64:388, 2015: Maeda, Gut, 66:1721, 2017). In this study, we attempted to predict the risk of primary gastric cancer by performing a new multicenter prospective study. We recruited 1,880 healthy people, after Helicobacter pylori eradication, with a clinically high risk of gastric cancer. Biopsy specimens were obtained from the antrum and body, and the methylation level of RIMS1, which is a preselected epigenomic risk marker for this study, was measured in 1,757 participants. The participants are annually being followed-up to detect primary gastric cancer, for 5-8 years. Currently, the median follow-up is 4.05 years, and 27 people have developed primary gastric cancers (as of September 2022). The results of statistical analysis are being determined. This study will establish the clinical utility of a cancer risk diagnosis by epimutation burden in normal tissue, and is promising for application in various inflammation-associated cancers. Citation Format: Harumi Yamada, Masahiro Maeda, Seiichiro Abe, Taichi Shimazu, Takayuki Ando, Kazunari Murakami, Shinji Tanaka, Takao Maekita, Osamu Inatomi, Ken Sugimoto, Tetsuro Kawagoe, Nobutake Yamamichi, Toshikazu Ushijima. Cancer risk diagnosis by epimutation burden: a multicenter prospective study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6014.
Abstract 176: Generation and maintenance of anaplastic thyroid cancer spheroids from human cancer cells
Authors: Jiangnan Hu, Chandrayee Ghosh, Electron Kebebew
Journal: Cancer Research (2023)

Abstract Background: Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer. Despite advances in tissue culture techniques, a robust model for thyroid cancer spheroid culture is yet to be developed. Here, we described a protocol to generate tumor spheroids from human ATC cells and excising cell lines. Methods: Using four established ATC cell lines (8505C, SW1736, C643 and THJ-16T) and one clinical tumor sample derived ATC cells, we created an efficient and cost-effective 3D culture system that can enhance our understanding of ex vivo treatment response. Results: We found that all four cell lines can readily form spheroids in culture with unique morphology, size, and cytoskeletal organization. We observed both cohesive (dense and solid structures) and dis-cohesive (irregularly shaped structures) spheroids within the same culture condition across different cell lines. BRAFWT ATC spheroids grew in a cohesive pattern, while BRAFV600E- mutant ATC spheroids show dis-cohesive organization. In the patient-derived spheroids (BRAFV600E- mutant ATC), we observed both growth patterns with mostly the dis-cohesive type. Phase-contrast images taken over time suggest that the cohesive ATC spheroids seem to be clonally derived, allowing the study of tumor heterogeneity. Furthermore, the ATC spheroids we established can maintain the 3D structures in the culture medium. Conclusion: Our study describes the development of a robust spheroid system from established ATC cell lines and freshly acquired patient tumor samples. We show that combining 3D culture with traditional 2D methods provides a complementary and powerful approach to the future drug screening and mechanism studies in the ATC. Citation Format: Jiangnan Hu, Chandrayee Ghosh, Electron Kebebew. Generation and maintenance of anaplastic thyroid cancer spheroids from human cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 176.
Abstract 2082: DNAfusion: An R/Bioconductor package for increased sensitivity of detecting EML4-ALK gene fusions in liquid biopsies from cancer patients
Authors: Christoffer Trier Maansson, Emma Roger Andersen, Maiken Parm Ulhoi, Peter Meldgaard, Boe Sandahl Sorensen
Journal: Cancer Research (2023)

Abstract EML4-ALK gene fusions are oncogenic drivers in non-small cell lung cancer (NSCLC). Liquid biopsies containing circulating tumor DNA (ctDNA), including EML4-ALK, can be used to study tumor dynamics with next-generation sequencing (NGS). However, the sensitivity of EML4-ALK detection in liquid biopsies varies between different pipelines and analysis tools. We developed an R/Bioconductor package, DNAfusion, which can be applied to BAM files generated by commercially available NGS pipelines, such as AVENIO. 48 blood samples from a training cohort consisting of 41 stage IV EML4-ALK positive NSCLC patients and 7 healthy controls were used to develop DNAfusion. DNAfusion detected EML4-ALK in significantly more samples compared to AVENIO (sensitivity = 61.0% vs. 36.6%, P = 0.046). The newly identified EML4-ALK positive patients were verified using droplet digital PCR. DNAfusion was subsequently validated in a blinded validation cohort comprising 24 EML4-ALK positive and 24 EML4-ALK negative stage IV NSCLC patients. DNAfusion detected significantly more EML4-ALK individuals in the validation cohort compared to AVENIO (sensitivity = 62.5% vs. 29.2%, P = 0.042). DNAfusion demonstrated a specificity of 100% in both the training and the validation cohorts. Monitoring EML4-ALK variants with AVENIO and DNAfusion in serial blood samples from 24 stage IV EML4-ALK positive patients during treatment (n = 72), revealed that DNAfusion can detect EML4-ALK variants at clinically critical timepoints, otherwise missed by AVENIO. Here we present DNAfusion, which increases sensitivity of EML4-ALK detection in liquid biopsies and can be implemented downstream of commercially available NGS pipelines. The high sensitivity of DNAfusion is a necessity for analytical tools used to monitor ctDNA in serial plasma samples in order to implement liquid biopsies in the clinic. The simplistic way of operating the R package makes it easy to set up in the clinical setting enabling wider expansion of liquid biopsy and NGS based diagnostics. Citation Format: Christoffer Trier Maansson, Emma Roger Andersen, Maiken Parm Ulhoi, Peter Meldgaard, Boe Sandahl Sorensen. DNAfusion: An R/Bioconductor package for increased sensitivity of detecting EML4-ALK gene fusions in liquid biopsies from cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2082.
Abstract 4318: Cancer cell communication with macrophages prevents T cell activation during emergence of cell cycle therapy resistance
Authors: Jason I. Griffiths, Patrick A. Cosgrove, Eric Medina Castaneda, Aritro Nath, Jinfeng Chen, Frederick R. Adler, Jeffrey T. Chang, Qamar J. Khan, Andrea H. Bild
Journal: Cancer Research (2023)

Abstract By corrupting signals for growth and survival, evolving cancer cells can engineer the tumor microenvironment (TME) to promote treatment resistance. However, the specific interactions between malignant and non-malignant cells that predispose drug resistance and their changes during treatment remain widely unknown. Here we examine the composition, communication, and phenotypic diversity of tumor-associated cell populations in serial biopsies from early-stage ER+ breast cancers. We used single-cell RNA sequencing to profile over 400 thousand malignant and non-malignant cells from patient tumor samples obtained before, during and after treatment. The patients received either endocrine therapy (letrozole) alone or in combination with a CDK4/6 cell cycle inhibitor (ribociclib). Our analyses reveal that cancer cells from ribociclib-resistant tumors stimulate macrophage differentiation towards an immune-suppressive phenotype through upregulation of a diversity of cytokines and growth factors. The macrophage phenotype shift leads to reduced crosstalk with cytotoxic T-cells via IL-2/15/18 receptors, diminishing T-cell activation and recruitment. These results indicate that cancer communications promoting an immune-cold TME predispose tumors to develop CDK4/6 cell cycle inhibitor resistance, and that the beneficial effects of blocking cancer cell proliferation must be balanced against their inhibitory effect on immune cell division and activation. An optimal treatment strategy will require coupling the prevention of cancer division with activation of an effective cytotoxic T-cell response. Citation Format: Jason I. Griffiths, Patrick A. Cosgrove, Eric Medina Castaneda, Aritro Nath, Jinfeng Chen, Frederick R. Adler, Jeffrey T. Chang, Qamar J. Khan, Andrea H. Bild. Cancer cell communication with macrophages prevents T cell activation during emergence of cell cycle therapy resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4318.
Abstract 5951: The correlation between single nucleotide polymorphism of chemokine receptor and ligand and infiltrating immune cells on tumor microenvironment of gastric cancer
Authors: Sunjoo Yoon, Ju Hyun Lee, Minsu Kang, Hyeon Jeong Oh, Jiwon Koh, Hye Seung Lee, So Hyun Kang, Young Suk Park, Keun-Wook Lee, Jin Won Kim
Journal: Cancer Research (2023)

Abstract Objective: Chemokines play roles in many normal biological processes, such as hematopoietic cell genesis and leukocyte migration and homing. Chemokines could be responsible for eliciting local accumulation of immune cells within tumor microenvironment. In this study, we examine if genetic variations in chemokine receptor and ligand are associated with infiltrations of immune cells on tumor microenvironment in gastric cancer. Methods: In 356 gastric cancer patients who received curative surgery followed by adjuvant chemotherapy, total 105 single nucleotide polymorphisms (SNP) in a chemokine ligand and chemokine receptor locus within 16 genes (CXCR4, CXCR2, CXCR1, CX3CR1, CCR8, CCR9, CCR3, CCR2, CCR5, CCRL2, CCR6, CXCR5, CCR6, CXCR6, CCR7, DARC) were genotyped from peripheral blood sample. Total 11 immune markers such as CD3, CD4, CD8, FOXp3, CD68, CD163, L-selectin, i-NOS, ADMA17, Arginase, CD45RO were analyzed for deposition of immune cells according to SNP of chemokine receptor and ligand. Levels of immunohistochemistry staining were quantified by Image Analysis Toolbox and density of immune cells infiltration was calculated. Results: 32 SNP locus of 8 genes (such as CXCR1, CXCR2, CCR3, CCR2, CCR5, CCRL2, CCR6. CXCR5) were selected using 25% cut-off value of minor allele frequency (MAF). Among 8 genes, CCR5 was the most relevant gene for immune cell infiltration on tumor microenvironment. Intron1-2545G&amp;gt;A (rs1799987) were associated with increased accumulation of CD3+, CD68+ and FOXp3+ cells compared to recessive carriers of the common allele. In CCR5 SNP that contained the common alleles of intron1-2549 G&amp;gt;T (rs2734648) and exon2A-2081 A&amp;gt;G (rs1800023), CD3+, CD4+, CD8+ and FOXp3+ cells were infiltrated more than minor alleles. Conclusions: The associations between infiltration of immune cells and SNP of chemokine receptor and ligand in gastric cancer were shown. Particularly, CCR5 SNP may be most relevant for correlation with infiltration of immune cells on tumor microenvironment. Citation Format: Sunjoo Yoon, Ju Hyun Lee, Minsu Kang, Hyeon Jeong Oh, Jiwon Koh, Hye Seung Lee, So Hyun Kang, Young Suk Park, Keun-Wook Lee, Jin Won Kim. The correlation between single nucleotide polymorphism of chemokine receptor and ligand and infiltrating immune cells on tumor microenvironment of gastric cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5951.
Abstract 6007: <i>p16</i> epimutation modulates the tumor microenvironment and promotes malignancy of <i>Apc</i>-mutant colon cancer
Authors: Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B. Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J. Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Wei Li, Lanlan Shen
Journal: Cancer Research (2023)

Abstract Methylation of the p16 promoter resulting in mitotically stable gene silencing—known as p16 epimutation—is the most common epigenetic event in human colorectal cancer (CRC) and is also common in normal-appearing colonic mucosa of aging individuals. However, the functional role of p16 epimutation in CRC carcinogenesis is not completely understood. Here, using a mouse model of engineered p16 promoter hypermethylation, we show that p16 epimutation cooperates with mutant Apc to promote colon cancer development. Mice carrying combined Apc mutation and p16 epimutation display significantly shortened survival and increased tumor growth compared to those with Apc mutation only. Moreover, colon tumors from these animals express increased levels of programmed death-ligand 1 (Pdl1). Single-cell RNA sequencing (scRNA-seq) analysis further revealed the presence of dysfunctional cytotoxic CD8+ T cells together with Foxp3+ Tregs and γδT17 cells, which promote an immunosuppressive tumor microenvironment (TME). Lastly, we show that a combined therapy using an inhibitor of DNA methylation and a PD-L1 immune checkpoint inhibitor is more effective for improving survival in tumor-bearing mice than anti-PD-L1 treatment alone. These findings provide a mechanistic rationale for targeted epigenetic and immunotherapy in CRC patients, with the potential to improve colon cancer treatment. Citation Format: Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B. Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J. Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Wei Li, Lanlan Shen. p16 epimutation modulates the tumor microenvironment and promotes malignancy of Apc-mutant colon cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6007.